Summary: New research indicates that balance and walking problems seen in Alzheimer’s disease may not always start in the brain. Instead, these symptoms can originate in the peripheral nervous system, where nerves connect to muscles.
Using advanced “human-on-a-chip” technology, researchers showed that genetic mutations linked to familial Alzheimer’s can directly impair the nerve-to-muscle connection, independently of the brain or spinal cord.
Key Findings
- Beyond the Brain: For the first time, scientists have demonstrated that peripheral nervous system deficits can result directly from Alzheimer’s-related mutations.
- Why Some Treatments Fall Short: Therapies aimed solely at clearing brain plaques and tangles may not resolve movement impairments that originate in peripheral nerves.
- Human-on-a-Chip Advantage: Conventional animal models often fail to reproduce human Alzheimer’s progression. Lab-grown systems built from human stem cells can more closely recreate human biology and reveal effects missed in animals.
- The Reflex Connection: The study implicates breakdown at the neuromuscular junction (NMJ) — the same circuit tested by a physician’s knee reflex — suggesting that reflex-related hardware may be damaged at the cellular level in Alzheimer’s.
Source: University of Central Florida
UCF researchers report evidence that some movement-related symptoms of Alzheimer’s disease may begin outside the brain, with implications for how we detect and treat the disease.
This work, funded by the National Institute on Aging at the National Institutes of Health, was led by Professor James Hickman and Research Professor Xiufang “Nadine” Guo from the UCF Nanoscience Technology Center.
In partnership with Hesperos, a company that manufactures microphysiological systems, the team used laboratory-grown human cell models to study how familial Alzheimer’s mutations affect movement without input from the brain or spinal cord.
The study was published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
“Motor deficits may be an earlier indication [of Alzheimer’s],” Guo says. “If we can detect those changes and intervene sooner, we may be able to delay the appearance of central nervous system symptoms.”
How Movement and Alzheimer’s Are Connected
Familial Alzheimer’s (fAD) is a rare inherited form of the disease that typically appears between ages 40 and 65. While Alzheimer’s is primarily associated with memory loss and dementia, clinicians have long observed that some patients develop balance, gait or other motor changes years before cognitive decline becomes obvious. Those early symptoms raise the possibility that parts of the disease process begin outside the brain.
Using the microphysiological approach, the researchers found that diseased motor neurons carrying fAD mutations were sufficient to disrupt the NMJ and impair muscle activation. These effects occurred even when the brain and spinal cord were not present in the system, indicating a peripheral origin for some motor deficits.
“This is the first time it’s been shown that deficits in the peripheral nervous system can arise directly from these mutations,” Hickman explains. “That suggests drugs focused only on the brain may not correct peripheral problems.”
Guo adds that preserving motor function could also support brain health, since physical activity is linked to better cognitive outcomes.
How Researchers Build Human Disease Models in the Lab
To investigate peripheral effects, the team used a “human-on-a-chip” platform produced by Hesperos. These miniature systems recreate how human cells interact, enabling functional studies that better reflect human biology than many animal tests.
The researchers constructed a neuromuscular junction-on-a-chip: a dual-chamber device that models the connection between motor neurons and skeletal muscle cells. Crucially, the system excluded the brain and spinal cord so investigators could isolate peripheral mechanisms.
They paired healthy human skeletal muscle cells with motor neurons derived from induced pluripotent stem cells (iPSCs) that carried familial Alzheimer’s mutations. The resulting impairment of neuromuscular function supports the idea that some Alzheimer’s-related motor issues begin in peripheral circuits.
Why the Nerve-to-Muscle Connection Matters
The NMJ is where a nerve instructs a muscle to contract. Damage at this site reduces strength, coordination and endurance and can produce symptoms similar to those clinicians see in early movement disorders.
In the study, researchers measured how consistently nerve signals produced muscle contractions and how long muscles could sustain activity before fatiguing. These measures mirror clinical tests used to assess motor function and reflex integrity.
“You can’t move unless the motor circuit works,” Hickman says. “When a doctor taps your knee to check your reflex, they’re testing that same connection.”
The Future of ‘Human-on-a-Chip’ Technology
The investigators believe microphysiological systems will play an increasing role in drug development because they use human cells and provide functional readouts that better predict human responses than many animal models.
For Hickman, this work culminates decades of research aimed at understanding disease mechanisms and improving therapies. “These systems let us study disease in a way that mirrors the human body,” he says, “and that’s essential for developing more effective treatments.”
Key Questions Answered:
A: Not exactly. Alzheimer’s remains a neurological disease, but these results show it can affect the entire nervous system, including peripheral connections to muscles. Peripheral “wiring” can fail alongside or even before central nervous system changes.
A: The researchers suggest that maintaining motor function could support brain health. Intervening at the nerve-muscle level early might help delay more severe cognitive symptoms, though clinical trials would be needed to confirm this.
A: It is a microphysiological system that uses live human cells to recreate organ-level functions on a chip. This approach lets scientists study how diseased human nerves interact with healthy muscles without relying on animal models.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context was provided by the news team.
About this Alzheimer’s disease research news
Author: Margot Winick
Source: University of Central Florida
Contact: Margot Winick – University of Central Florida
Image: The image is credited to Neuroscience News
Original Research: Open access. “Evaluating the peripheral nervous system pathology of Alzheimer’s disease utilizing a functional human NMJ microphysiological system” by Akhmetzada Kargazhanov, Romy Aiken, Kenneth Hawkins, Rafael Lopez, Ahmad Nawaz, Gaurav Srivastava, Chase Miller, Will Bogen, Christopher Long, David Morgan, Xiufang Guo, James Hickman. Alzheimer’s & Dementia. DOI: 10.1002/alz.71281
Abstract
Evaluating the peripheral nervous system pathology of Alzheimer’s disease utilizing a functional human NMJ microphysiological system
INTRODUCTION
Alzheimer’s disease is classically a central nervous system neurodegenerative disorder that leads to dementia, but motor deficits also occur. It has been unclear whether peripheral motor problems are a consequence of upstream central nervous system decline or whether they can arise within the neuromuscular circuit itself. This study created a model to evaluate neuromuscular pathology in familial Alzheimer’s using a functional NMJ system.
METHODS
Induced pluripotent stem cell (iPSC) motor neurons carrying familial Alzheimer’s mutations were combined with healthy iPSC-derived skeletal myoblasts in a dual-chamber neuromuscular junction system. Formation and function of the NMJs were evaluated using readouts that align with clinical measures of motor function.
RESULTS
Functional testing showed that NMJs formed with fAD motor neurons displayed substantial deficiencies in neuromuscular function, ranging from severe deficits with the PSEN1 A246E mutation to moderate impairments with the APP K595N/M596L mutation.
DISCUSSION
These results confirm that familial Alzheimer’s mutations can cause NMJ dysfunction, supporting the view that motor deficits can be initiated independently of cognitive decline. The findings highlight the importance of examining peripheral nervous system pathology alongside central nervous system changes when studying Alzheimer’s disease and developing treatments.